The goal of this project is to understand aspects of the pathogenesis of herpes simplex virus (HSV) infection in the nervous system including the mechanism by which this neurotropic virus is regulated within neuronal and non~neuronal cells during acute and long~term infections. A further objective is to understand the relationship between HSV infection and disease. During FY 1993, studies to develop and analyze transgenic mouse models of HSV~1 pathogenesis were continued. The primary goal was to investigate the mechanism by which HSV~1 replication is regulated by specific host and viral transcriptional regulatory proteins during initial epithelial and subsequent nervous system infections. Analysis of transgenic mice containing the HSV~1 major immediate early promoter sequence fused to the E. coli beta galactosidase coding sequence has shown that HSV~1 can persist in non~neuronal cells with expression of the immediate early promoter. Viral DNA in chronically infected non~neuronal cells is localized to inflammatory lesions and appears to be related to production of the inflammation. This observation may also apply to long~term infections of non~neuronal cells in the CNS and could afford a new mechanism by which HSV could produce chronic inflammation within the CNS. In transgenic mice expressing the homeodomain protein Hox 1.3, we previously showed that the pathogenesis of acute HSV~1 infection was profoundly enhanced. Preliminary experiments in these mice have shown that reactivation from latent HSV~1 infection occurs more efficiently in transgenic mice expressing Hox 1.3 than in non~transgenic littermates. This observation is being followed up since it is important to know whether induction of transcription of HSV~1 immediate early genes is a key to reactivation of virus from latency in neurons.